The effect of SDF‐1α on low dose BMP‐2 mediated bone regeneration by release from heparinized mineralized collagen type I matrix scaffolds in a murine critical size bone defect model

Abstract

The treatment of critical size bone defects represents a challenge. The growth factor bone morphogenetic protein 2 (BMP-2) is clinically established but has potentially adverse effects when used at high doses. The aim of this study was to evaluate if stromal derived factor-1 alpha (SDF-1α) and BMP-2 released from heparinized mineralized collagen type I matrix (MCM) scaffolds have a cumulative effect on bone regeneration. MCM scaffolds were functionalized with heparin, loaded with BMP-2 and/or SDF-1α and implanted into a murine critical size femoral bone defect (control group, low dose BMP-2 group, low dose BMP-2 + SDF-1α group, and high dose BMP-2 group). After 6 weeks, both the low dose BMP-2 + SDF-1α group (5.8 ± 0.6 mm³, p = 0.0479) and the high dose BMP-2 group (6.5 ± 0.7 mm³, p = 0.008) had a significantly increased regenerated bone volume compared to the control group (4.2 ± 0.5 mm³). There was a higher healing score in the low dose BMP-2 + SDF-1α group (median grade 8; Q1-Q3 7-9; p = 0.0357) than in the low dose BMP-2 group (7; Q1-Q3 5-9) histologically. This study showed that release of BMP-2 and SDF-1α from heparinized MCM scaffolds allows for the reduction of the applied BMP-2 concentration since SDF-1α seems to enhance the osteoinductive potential of BMP-2. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2126-2134, 2016.

Strontium enhances BMP‐2 mediated bone regeneration in a femoral murine bone defect model

“…However, these supraphysiological BMP‐2 doses are associated with several potential adverse effects—ectopic bone formation in particular. The modification of heparinized MCM scaffolds has been shown to attenuate the initial burst of BMP‐2 and to facilitate a long‐term release for up to 6 weeks . This effect allows the reduction of the applied BMP‐2 concentration, which could prevent concentration‐related side effects.…”

“…These drawbacks can be attenuated by a retarded BMP‐2 release from the biomaterial, which has been the focus of recent studies by our group. The modification of MCM with the glycosaminoglycan heparin can prevent the initial burst of growth factors with heparin‐binding domains and enable a sustained release over weeks in vitro ; a sustained release of BMP‐2 over 6 weeks has been verified in vitro . Besides the retarding effect on the growth factor release, heparin modification has also been shown to significantly promote the proliferation and osteogenic differentiation of mesenchymal stroma cells in vitro .…”

“…The interconnected porosity and average pore size of 180 μm have been shown by several in vitro studies to promote proliferation and osteogenic differentiation of human bone marrow‐derived stromal cells (hBMSC) . Scaffold resorption and new bone formation at the defect site have been demonstrated in vivo . MCM has recently shown by Quade et al to be easily modified with strontium by substituting calcium with strontium in the mineralization batch, leading to a shift of the mineral phase from nanocrystalline hydroxyapatite (Sr0) over poorly crystalline Sr‐rich phases toward a mixed mineral phase (Sr100), consisting of an amorphous strontium phosphate (identified as Collin's salt, Sr 6 H 3 (PO 4 ) 5 × 2 H 2 O, CS) and highly crystalline strontium hydroxyapatite (Sr 5 (PO 4 ) 3 OH, SrHA) .…”

The Good the Bad and the Ugly of Glycosaminoglycans in Tissue Engineering Applications

“…In addition, the low cost, easy availability, and status of heparin as an already FDA- and EMA-approved product, has meant that researchers are harnessing its properties, preferentially over that of other GAGs (such as HS) to improve growth factor delivery [188,189,192,194,440]. Gaining particular prominence is the use of heparin-loaded delivery vehicles for skeletal TE, where biomaterials decorated with heparin have been extensively studied both in vitro and in vivo, for their ability to reduce the dosing requirements and improve the therapeutic potential of BMPs, such as BMP2 [188,189,194,455,456,457,458,459,460]. Most of these studies have shown very promising results, with heparin-loaded biomaterials improving BMP2 delivery, release, and osteogenic potential.…”

A Dermal Equivalent Engineered with TGF‐β3 Expressing Bone Marrow Stromal Cells and Amniotic Membrane: Cosmetic Healing of Full‐Thickness Skin Wounds in Rats

“…The vessels were identified by lumen-like structures filled by erythrocytes (33). Tissue specimens were then fixed in 10% formaldehyde, dehydrated in graded alcohol solutions of 50, 70, 90, 96, and 100%, cleared in xylene (Merck, Darmstadt, Germany), and embedded in paraffin (Merck).…”